DESCRIPTION: (Applicant's Abstract) The objective of the proposed research is to synthesize and evaluate the preclinical biological and behavioral effects of novel compounds targeted for development as new cocaine abuse therapeutic agents. Novel compounds will be prepared and tested in vitro and in vivo paradigms to investigate the heterogeneous character (low affinity and high affinity binding components) of the dopamine transporter associated with cocaine binding. This study should elucidate the behavioral effects and abuse liability associated with the high affinity site and the low affinity site corresponding to cocaine binding. A greater understanding of these effects should aid in the development of new cocaine abuse therapeutic agents. Novel compounds will be synthesized to be developed as potent selective dopamine transporter ligands which can be rapidly transported into the brain and are long-lived in in vivo. The compounds will be tested in in vitro and in vivo paradigms to explore the effects of drug transport on abuse liability. In addition, dopamine transporter selectivity (versus serotonin transporter) and secondary receptor binding (sigma-receptors) will be investigated. It is anticipated that a highly selective dopamine transporter ligand with a fast onset of activity will be identified for development as a therapeutic agent for acute cocaine overdose as well as chronic cocaine addiction.